Shaban Eman, Bayliss George, Malhotra Deepak K, Shemin Douglas, Wang Li Juan, Gohh Reginald, Dworkin Lance D, Gong Rujun
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
Transplant Center, University of Michigan, Ann Arbor, Michigan, USA.
Kidney Dis (Basel). 2018 Nov;4(4):205-213. doi: 10.1159/000490703. Epub 2018 Jul 31.
Organ transplantation is considered the ultimate therapy for end-stage organ disease. While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes. Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression.
Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice. The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation. Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance. Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance-inducing features of Tregs. A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance. In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections. Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status. Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant.
Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients.
器官移植被认为是终末期器官疾病的终极治疗方法。虽然药物免疫抑制是延长移植物存活的治疗策略的主要手段，但长期使用免疫抑制药物存在器官毒性、恶性肿瘤、严重机会性感染和糖尿病的风险。在实体器官移植中促进受体耐受的疗法能够通过消除长期免疫抑制的需求来改善患者预后。
建立对同种异体移植物的耐受已成为一个深入研究的领域，并且将是临床实践中的理想治疗方法。天然致力于执行免疫调节的T细胞亚群的发现导致了对其在移植免疫发病机制中的作用的进一步研究。证据表明，调节性T细胞（Tregs）从根本上参与促进同种异体移植物耐受。尽管具有挑战性，但表征Tregs特异性标志物的努力已将Foxp3基因表达确定为促进Tregs耐受诱导特征的关键步骤。已经测试了多种方法，包括基于靶向糖原合酶激酶3β信号通路或激活黑皮质素能通路的方法，作为促进Treg谱系定向和维持以及促进免疫耐受的一种方式。为了在临床实践中有效，Tregs必须是同种异体特异性的并且具有特定的表型，以避免抑制免疫系统的其他方面或增加恶性肿瘤或感染的风险。多项实验和临床研究已经证明了目前使用的免疫抑制剂对Tregs的免疫调节活性及其Foxp3表达状态的影响。诱导耐受性Tregs以诱导移植耐受的药理学方法，包括表观遗传疗法，正日益受到关注。
促进Treg功能和存活的疗法可能代表了在移植患者中实现免疫耐受的一种新策略。
